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Derek Lowe's commentary on drug discovery and the pharma industry. An editorially independent blog from the publishers of Science Translational Medicine. All content is Derek’s own, and he does not in any way speak for his employer.

Alzheimer's Disease

The Coming Battle Over Alzheimer’s Disease

Solanezumab is a story that won’t go away. Eli Lilly’s antibody therapy for Alzheimer’s is the subject of a lot of arguing among investors: some people (and I’m one of them) think that there is no strong evidence for its efficacy, not yet, and that the amount of time and effort devoted to finding that out means that there likely isn’t any meaningful efficacy to be found. Others are more optimistic, which is why Lilly’s stock has risen in recent months.
The latest point of contention is an independent analysis of biomarker data which came out this week at a conference in Monaco. This suggests that there was a meaningful change in the amount of circulating beta-amyloid after treatment, which could mean that the antibody was working as planned to increase clearance of soluble amyloid, thus altering the amyloid balance in the CNS. It should be noted that this line of attack depends on several factors – first among them, that amyloid is a causative factor in Alzheimer’s, and secondly, that clearing it from the periphery can affect its concentration and distribution inside the brain. There’s evidence for both of these, and there’s evidence against both of them. Such questions can only be answered in the clinic, and I’m glad that Lilly, Roche/Genentech, and others are trying to answer them.
What I want to focus on today, though, is an issue that comes up in passing in the Fierce Biotech link above:

Biomarkers and pooled data may help support further studies of the drug, as well as other programs that rest on the beta amyloid hypothesis, but they don’t prove that solanezumab works as hoped. Nevertheless, the first sign of success in this field has fueled tremendous enthusiasm that something in the pipeline could eventually work–perhaps even pushing regulators to approve new therapies with something less than clear efficacy data. And any newly approved drug would find a massive market of millions of desperate patients.

That’s a big “perhaps”, one that’s worth tens of billions of dollars. What I worry about is pressure building for the FDA to approve an Alzheimer’s therapy (solanezumab or something else) based on these hints of mechanistic efficacy. The problem is, solanezumab hasn’t shown much promise of improving the lives of actual Alzheimer’s patients. Lilly’s own trials showed a possible improvement in a measure of cognitive decline, but this did not show up again in a second patient group, even when they specifically modified the endpoints of the trial to look for it. And neither group showed any functional effects at all, which I think are what most Alzheimer’s patients (and their family members) would really want to see.
But there really is such a huge demand for something, anything, with any hint of hope. People would line up to buy anything that got FDA approval, no matter how tenuous the evidence was. And that puts the agency in a very tough position, similar to the one it was in with the Avastin breast cancer issue. Update: there was, to be sure, more of a safety question with Avastin at the same time. You can argue that one of the main purposes of the agency is to make sure that medicines that people can be prescribed in this country will actually do some good, rather than raise hopes for nothing. You could also argue that responsible adults – and their physicians, and their insurance companies – should be able to make such choices for themselves, and should be able to spend their time and money in the ways that they best see fit. You could argue that companies with marginally effective (or ineffective) therapies face a huge moral hazard, in that their incentives are to get such treatments onto the market whether they do anyone else any good or not. None of these are foolish positions, but they are also, in places, mutually incompatible. Alzheimer’s disease might well turn into the next place in which we thrash them out.

17 comments on “The Coming Battle Over Alzheimer’s Disease”

All good points. However, the safety profiles for Avastin and Solanezumab are radically different. Also, the efficacy arguments for Solanezumab are bolstered by the deCode studies in Iceland, which are difficult to explain if amyloid does not have at least some causative role.

“You could also argue that responsible adults – and their physicians, and their insurance companies – should be able to make such choices for themselves, and should be able to spend their time and money in the ways that they best see fit.”
Problem is, AD affects groups (i.e. elderly) that tend to vote in large numbers and associate with powerful lobbies (AARP). There would be tremendous pressure on insurance plans to cover a FDA-approved medication, especially for a disorder as devastating as AD. This would end up being a very heavy cost born by all of society, not just responsible adults, physicians and insurance companies. We all pay into the overall cost of insurance through our own premiums and payroll taxes.
If the drug/antibody was only marginally effective on a biomarker level, without providing any improvement on quality of life or functionality, we as a society would be adding enormously to the national cost of healthcare and deriving little to no benefit. It would be a shame if an expensive antibody were approved based on political pressure to provide a hint of hope.

These were the the same pressures/arguments that led to the FDA approval of tacrine for the same indication even when a member of the Advisory Committee publically stated “I wouldn’t give it to my dog”. Read Ben Goldacre’s book “Bad Pharma” – Lilly has violated every caveat listed in his chapter on bad trials in analyzing the solaneuzumab data.
As to DeCode bolstering the amyloid hypothesis- how many associations has this company made that have proved to be irrelevant? Answer – a lot.

..People would line up to buy anything that got FDA approval, no matter how tenuous the evidence was. All those investors and Eli Lilly is betting on that premise. I always felt that a marginally effective medication with little or no adverse effects stood a better chance for approval. Proof? Pfizer’s Aricept.

There may well be a ‘battle coming’ in Alzheimer’s, but I fear it would be post approval. Should the FDA agree to approve a drug like Solanezumab, what you will likely have is very expensive, marginally effective treatment for a very large and desperate population. It would be a reimburser’s nightmare, as they would be damned if they approve reimbursement, as well as if they don’t.
Zz

Most of the top researchers in the alzheimer’s field thinks that small oligomers of A-Beta are the toxic species in the disease, whereas amyloid aggregates are just a later symptom, and potentially even protective. There’s lots of evidence for this. I don’t know why it’s so hard for people that cover drug discovery to get this fact.

ronathan,
The reason people are skeptical of the amyloid hypothesis is that amyloid doesn’t cause neuronal loss in mice. This is despite the fact that amyloid can be toxic to cultured mouse neurons in vitro. The amounts of amyloid needed to demonstrate toxicity in vitro are however orders of magnitude higher than the levels ever reached in vivo. These observations are almost universally accepted.
Several work-arounds have been proposed to reconcile these observations with the universal presence of amyloid plaques in the brains of people with Alzheimer’s, including enhanced toxicity of certain minor species of amyloid or aggregated forms, and the relatively short lifespan of mice, among others.
Thus, from a strictly scientific perspective, it remains to be experimentally demonstrated that the amyloid peptide is the toxic agent in AD.

Maybe I’m missing something…
Isn’t it pretty well known from studies targeting cytokines and other soluble targets, what happens to circulating levels of a soluble target upon binding to antibody? The circulating concentrations go up. I would be much more comfortable interpreting as a 1/2 life extension imparted by the Fc portion of the bound antibody before I went down the efficacy road. However that probably doesn’t sound as nice to investors…

[ Science vol. 337 p. 1488 ’12 (18 Oct ’12) ] One of the 3 antiamyloid therapies to be tried in the DIAN trial (see below) will actually be solanezumab. Importantly, solanezumab will be randomly given to the 80% of the participants who presently have no symptoms. DIAN should give us excellent information (after a decade or two) about this class of drugs.
DIAN (Dominantly Inhertied Alzheimer Network) is recruiting ‘up to’ 400 members of families with early onset Alzheimer’s. 50% of the group will be chosen so that they have a mutation on one of 3 genes (PSEN1, PSEN2, APP) known to cause autosomal dominant Alzheimer’s disease.

Yesterday, TauRx launched trials for a tau-related drug for Alzheimer’s disease–in 15 countries. Psychiatrist/CEO Claude Wischik believes Tau is a better–and earlier bet. I posted the press release on my Web site–http://harriscom.com—you can find the slides and audio of the presentation–and probably the press release– on the TauRx Web site at http://www.taurx.com.

More or less this is the mistake that has been made. Amyloid plaques or oligomers are present in most people with Alzheimer’s disease. Moreover, people with genes that lead to the production of amyloid plaques end up with Alzheimer’s disease, therefore amyloid plaques are the cause of Alzheimer’s disease. But the partial fallacy lies in taking one of the hallmarks of the disease as causation.
The key oxidant in Alzheimer’s disease is called peroxynitrite. The principal pathway to its formation is as follows: the phospholipase C mediated activation of Protein kinase C results in the increased production of superoxide anions and inducible nitric oxide which combine to form peroxynitrites. The pathway to the formation of amyloid plaques is phospholipase C activation which leads both to Protein kinase C activation and the release of intracellular calcium. Protein kinase C regulates the secretion of the amyloid precursor protein and a calcium driven enzyme cleaves it into oligomers which are then nitrated by peroxynitrites forming plaques (Kummer, et al. Nitration of tyrosine 10 critically enhances amyloid B aggregation and plaque formation). So if you inhibit phospholipase C beta and gamma you inhibit both the formation of plaques and in most cases peroxynitrites. Moreover, the plaques increase the formation of peroxynitrites because they entomb zinc and copper. The upshot of this is an increase in homocysteine levels and a decrease of superoxide dismutase which leads to an increase in both superoxide anions and inducible nitric oxide levels.
If you pull some of the plaques out early, you will see some slight slowing down of the disease, because you are slowing down the formation of peroxynitrites. But you are not going after the true cause of the disease directly. I will post the results of studies in which compounds (eugenol in rosemary essential oil and ferulic acid, coumaric acid, syringic acid, and vanillic acid in heat-processed ginseng) scavenged peroxynitrites and repaired part of the damage that they caused in people with Alzheimer’s disease.
Psychogeriatrics. 2009 Dec;9(4):173-9.
Effect of aromatherapy on patients with Alzheimer’s disease.
Jimbo D, Kimura Y, Taniguchi M, Inoue M, Urakami K.
SourceDepartment of Biological Regulation, School of Health Science, Faculty of Medicine, Tottori University, Yonago, Japan.
RESULTS: All patients showed significant improvement in personal orientation related to cognitive function on both the GBSS-J and TDAS after therapy. In particular, patients with AD showed significant improvement in total TDAS scores. Result of routine laboratory tests showed no significant changes, suggesting that there were no side-effects associated with the use of aromatherapy. Results from Zarit’s score showed no significant changes, suggesting that caregivers had no effect on the improved patient scores seen in the other tests.
Nutr Neurosci. 2012 Jul 9. [Epub ahead of print]
Heat-processed ginseng enhances the cognitive function in patients with moderately severe Alzheimer’s disease.
Heo JH, Lee ST, Chu K, Oh MJ, Park HJ, Shim JY, Kim M.
RESULTS: The treatment groups showed significant improvement on the MMSE and ADAS. Patients with higher dose group (4.5 g/day) showed improvements in ADAS cognitive, ADAS non-cognitive, and MMSE score as early as at 12 weeks, which sustained for 24-week follow-up.
If the pharmaceutical companies want to try to develop synthetic methoxyphenols that work better than natural methoxyphenols then o.k. But this manipulation of data to squeeze out even the slightest hint of slowing down the disease process in order to artificially inflate stock prices and to try to maneuver the FDA in to approving a drug of quite limited value is unseemly, especially considering that there are alternatives that actually treat the cause of the disease.

In regards to tau tangles, it too is a consequence of peroxynitrite formation. By oxidating g protein-coupled receptors and by nitrating tyrosine kinase receptors, peroxynitrites ensure the activation of GSK3 which hyperphosphorylates tau proteins. In addition, peroxynitrites nitrate tau proteins which means they cannot be reconstituted for proper neurotransmission.(Zhang, et al. Peroxynitrite induce Alzheimer’s-like tau modifications and accumulations in rat brain and its underlying mechanisms). The footprints of peroxynitrites are all over Alzheimer’s disease and this has been known since the mid-1990s.

Derek. You are making great points. The genetics of amyloid and Alzheimer’s disease (deCODE / Genentech data most recently) point to amyloid strongly as having a role in the disease. But the research community is struggling to figure out where one can successfully intervene on ABeta to block progression or reverse the disease. Since the antibodies to Abeta have failed in carefully planned clinical trials, you would expect that people would conclude that another approach is needed. However, for all the reasons you noted, people won’t give up on the antibodies until the data yields what people want to see in it. And then they will be approved. I call this the inverse witch hunt.

Derek. You are making great points. The genetics of amyloid and Alzheimer’s disease (deCODE / Genentech data most recently) point to amyloid strongly as having a role in the disease. But the research community is struggling to figure out where one can successfully intervene on ABeta to block progression or reverse the disease. Since the antibodies to Abeta have failed in carefully planned clinical trials, you would expect that people would conclude that another approach is needed. However, for all the reasons you noted, people won’t give up on the antibodies until the data yields what people want to see in it. And then they will be approved. I call this the inverse witch hunt.

Going for something that strictly has FDA approval is a fools game. The FDA is a joke. People need to start looking to other means that can actually help instead of waiting for the FDA to tell them what to take.

The DeCode data demonstrate that a lifelong approx 40% reduction of Abeta is protective. The reductions in Abeta that have been demonstrated in Ph3 with both bapi and sola are marginal, and are in patients who have been accumulating pathological levels of Abeta for years (decades??).